TY - JOUR
T1 - Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
AU - Dans, Madeline G.
AU - Boulet, Coralie
AU - Watson, Gabrielle M.
AU - Nguyen, William
AU - Dziekan, Jerzy M.
AU - Evelyn, Cindy
AU - Reaksudsan, Kitsanapong
AU - Mehra, Somya
AU - Razook, Zahra
AU - Geoghegan, Niall D.
AU - Mlodzianoski, Michael J.
AU - Goodman, Christopher Dean
AU - Ling, Dawson B.
AU - Jonsdottir, Thorey K.
AU - Tong, Joshua
AU - Famodimu, Mufuliat Toyin
AU - Kristan, Mojca
AU - Pollard, Harry
AU - Stewart, Lindsay B.
AU - Brandner-Garrod, Luke
AU - Sutherland, Colin J.
AU - Delves, Michael J.
AU - McFadden, Geoffrey I.
AU - Barry, Alyssa E.
AU - Crabb, Brendan S.
AU - de Koning-Ward, Tania F.
AU - Rogers, Kelly L.
AU - Cowman, Alan F.
AU - Tham, Wai Hong
AU - Sleebs, Brad E.
AU - Gilson, Paul R.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
AB - With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
UR - https://www.scopus.com/pages/publications/85196204192
U2 - 10.1038/s41467-024-49491-8
DO - 10.1038/s41467-024-49491-8
M3 - Article
C2 - 38890312
AN - SCOPUS:85196204192
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5219
ER -